Proteoglycans are major structural proteins that contribute to the integrity of the artery and affect the metabolism of atherogenic lipoproteins. Although interaction of lipoproteins with dermatan sulfate/chondroitin sulfate proteoglycans is widely believed to lead to lipoprotein retention, heparan sulfate proteoglycans (HSPGs) may be anti-atherogenic because they help form a barrier that prevents lipoprotein penetration into the artery wall. This Project contains 3 Aims to study the roles of HSPGs in regulation of atherogenic lipoproteins and arterial wall biology. In Aim 1 we propose experiments to modulate subendothelial HSPG(s) in monolayer cultures of endothelial cells and assess how this alters parameters of atherosclerosis including lipoprotein retention, endothelial permeability and migration of monocytes. The goal of Aim 2 is to assess atherosclerosis and lipoprotein metabolism in mice with a defect in perlecan production. Aim 3 will correlate expression of perlecan and its degradative enzyme heparanase in normal and diseased arteries from mice and humans, and will study the regulation of endothelial heparanase in vivo. Endothelial heparanase is expressed as a response to inflammatory stimuli in cultured cells, and we will assess whether this enzyme is likely to alter arterial biology during atherosclerosis. The theme of this Project is consistent with the overall goals of this SCOR to study atherogenic processes in genetically modulated mice. It also encompasses several sub-themes that interrelate with other projects of this SCOR. These include the biochemistry of lipoprotein retention by arterial molecules (Projects 1 & 7), studies of arterial wall enzymes (Project 1) and arterial effects of atherogenic and anti-atherogenic lipoproteins (Project 6 & 7). Moreover, the information obtained from the in vitro and animals studies will be used to relate HSPGs to human atherosclerosis by studying perlecan and heparanase gene expression in human arteries.